Oxidative damage to mitochondrial is a major source of toxicity in diseases such as Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD). Mitochondria are energy powerhouses of the cell, and decline in their function by oxidative damage is a common feature among neurodegenerative diseases. Despite years of effort, however, generic antioxidants have failed in clinical trials, and there are no effective therapeutics to offset the motor and cognitive decline in afflicted patients. The goal of this STTR application is to fill this medical gap. We have created a paradigm-shifting synthetic platform, in which antioxidants are targeted directly to MT, and reduce oxidative damage to their membranes, proteins, and DNA. The lead compound for this new platform is XJB-5-131, a synthetic, bi-functional molecule harboring a vehicle and a cargo. The cargo is the antioxidant portion, which neutralizes oxidative damage. The vehicle is a peptide mimetic that targets the antioxidant moiety directly to the mitochondrial membrane. XJB-5-131, crosses the blood-brain barrier, concentrates 600-fold in the MT, reduces oxidative damage in MT, improves motor function, prevents weight loss, and improves mitochondrial function in a mouse model of HD. These properties of synthetic XJB-5-131 overcome many sources of past failures, and render antioxidants a viable therapeutic strategy. Solano Pharmaceuticals will develop a series of analogues based on the lead compound, XJB-5- 131, which will be optimized for development as a clinical candidate. In Phase 1, we will identify the liabilities of the lead compound and efficacy facets of the molecule that need optimization. In Phase 2, we will focus on synthesis of molecules that improve the druglike properties of XJB-5-131. Successful analogues will be tested for efficacy in rodent models of HD and AD. The compounds that meet the required criteria will be moved into IND-enabling studies. AD alone is the largest growing burden of diseases in the United States, with nearly 6 million adults currently afflicted. Any viable therapeutic strategy would be a breakthrough with high clinical value.